A cephalosporin represented by the following formula ##STR2## mamely, (6R,7R)-7-[(Z)-2-(2-aminothiazol-4-yl) -2-methoxy-iminoacetamido]-3-[(Z)-2-(4-methylthiazol-5-yl)ethenyl]-8-oxo-5 -thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid is known as "Cefditoren", a generic name, and also is nominated as 7-[methoxyimino-2- (2-aminothiazol-4-yl) acetamido]-3-[2- (4-methylthiazol-5-yl) vinyl]-3-cephem-4-carboxylic acid in U.S. Pat. No. 4,839,350, Japanese patent No. 1698887 (Japanese patent publication "Kokoku" No. Hei-3-64503 published 7 October 1991) and European patent No. 0175610. The cephalosporin having the above formula (I) or a pharmaceutically acceptable salt thereof has a broad range of antibacterial spectra against gram-positive bacteria and gram-negative bacteria and can exhibit a high antibacterial activity against Staphylococcus aureus, Klebsiella pneumoniae and Haemophilus influenzae in particular, and thus is promising for use as injections.
While, it is known that arginine salt or lysine salt of certain acidic cephalosporins may be formulated into intramuscularly or subcutaneously injectable preparation with no substantial pain (U.S. Pat. No. 3,984,403), that a stable injection containing a certain cephalosporin together with lactose, citric acid, arginine and sodium chloride may be prepared (U.S. Pat. No. 5,254,545), and that several, crystalline and temperature-stable acid addition salts of 7-[.alpha.-(2-aminothiazol-4-yl)-.alpha.-(Z)-methoxyiminoacetamido]-3-[(1- methyl-1-pyrrolidino)methyl]-3-cephem-4-carboxylate may be formulated into the form of a physical admixture with lysine and/or arginine acting as a buffering agent and this admixture may be diluted with water to give an injectable preparation (U.S. Pat. Nos. 4,910,301; 4,994,451 and 5,244,891, and Japanese patent application first publication "Kokai" No. Hei-2-9885 laid open on Jan. 12, 1990). Cefditoren is not so highly stable to a fully satisfactory extent upon its storage when it is stored at ambient temperatures under dry air for long periods of time. Thus, Cefditoren can exhibit such low storage-stabilities that it can be discolored to a yellow color from its initial, faintly yellow to color less appearance and can be decomposed to an extent to show an undesirable reduction in its antibacterial activity, when Cefditoren has been stored at ambient temperatures under dry air or nitrogen gas for a long period of time. Cefditoren itself is of a low solubility in water at ambient temperatures, and a large amount of Cefditoren cannot be dissolved completely in water so that a clear aqueous solution containing Cefditoren at its medicinally effective concentration is difficult to be prepared.
In an attempt to prepare an injectable preparation containing Cefditoren or its pharmaceutically acceptable salt which may be dissolved in water just upon use to make up an injectable aqueous solution containing the cephalosporin, we, the present inventors, have made many experiments wherein Cefditoren or a pharmaceutically acceptable salt thereof alone is dissolved in water without addition of any stabilizing agent for the cephalosporin and the resulting aqueous solution is adjusted to a pH of 6.0.about.7.5 by addition of 0.1N aqueous sodium hydroxide or 0.1N aqueous hydrochloric acid and then lyophilized to afford a powdery preparation which is to be dissolved in a volume of injection-grade water upon use as an injectable aqueous solution, and which may be termed as "injectable powdery preparation for dissolution upon use", and wherein the powdery preparation as afforded is stored at ambient temperatures under dry air for long periods of time. It has been observed that the above-mentioned powdery preparation after the storage has been discolored to a yellow color and also been decomposed to show a reduction in its antibacterial potency as compared to its initial antibacterial potency of the powdery preparation before the storage, and that small quantities of water-insoluble matters can be left undissolved when the powdery preparation prepared as above is tried to be dissolved in water at room temperature before and after the storage. Thus, we have now found that the storage-stability of Cefditoren or a pharmaceutically acceptable salt thereof to be mixed in commercially distributable injections of Cefditoren is needed to be enhanced much as possible by devising a new measure to modify the composition or formulation of an injectable powdery preparation containing Cefditoren, in order to ensure that Cefditoren or a pharmaceutically acceptable salt thereof can be utilized safely and satisfactorily in a form of an injectable powdery preparation which is available in hospitals.
Therefore, an object of this invention is to provide such a new, stably storable and readily water soluble composition containing Cefditoren or a salt thereof, which is supplied in the form of a powdery preparation to be formulated into an injectable aqueous solution by dissolving in water by experts of the medicinal field in hospitals. Another object of this invention is to provide a new method for enhancing the storage-stability+of Cefditoren or a salt thereof present in a powdery composition containing the cephalosporin.